Use-dependent suppression of the nicotinic acetylcholine receptor response by the proadrenomedullin N-terminal 20-amino acid peptide in rat locus coeruleus neurons.
The effects of the proadrenomedullin N-terminal 20-amino acid peptide (PAMP) on the nicotinic acetylcholine (ACh) receptor (nAChR)-mediated inward current were investigated in neurons acutely dissociated from the rat locus coeruleus using whole-cell recording under voltage clamp. Nicotine and cytidine mimicked the ACh response, whereas the maximal response to dimethylphenylpiperazinium was lower in amplitude compared with that to ACh. Nicotine-induced current (I[nic]) was suppressed more effectively by mecamylamine than by hexamethonium. In addition, neither atropine nor alpha-bungarotoxin affected the I(nic). PAMP reversibly and noncompetitively suppressed the peak amplitude of 10(-4) M I(nic). PAMP concentrations for the threshold, half-maximal inhibition, and maximal inhibition of 10(-4) M I(nic) were 10(-8), 2.6 x 10(-7), and 10(-5) M, respectively. The peak amplitudes of 10(-4) M I(nic) elicited at 2-min intervals showed a gradual decline in the presence of 10(-7) M PAMP. This decline in the I(nic) was independent of the period of PAMP pretreatment. The suppression of I(nic) by PAMP did not show any voltage dependency at a holding potential (VH) of <0 mV, although the inhibitory effect was masked by the marked inward rectification of I(nic) at a VH of >0 mV. These results suggest that PAMP could thus be a unique endogenous peptide that antagonizes the nAChR in the CNS.
Nabekura
J
J
Department of Physiology, Kyushu University Faculty of Medicine, Fukuoka, Japan.
Murata
O
O
Ishibashi
H
H
Akaike
N
N
D053607:Adrenomedullin; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002038:Bungarotoxins / Q000494:pharmacology; D002478:Cells, Cultured; D003562:Cytidine / Q000494:pharmacology; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology; D005260:Female; D008125:Locus Coeruleus / Q000502:physiology*; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides; D011506:Proteins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*
D002038:Bungarotoxins; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D010455:Peptides; D011506:Proteins; D011978:Receptors, Nicotinic; D053607:Adrenomedullin; D004246:Dimethylphenylpiperazinium Iodide; D003562:Cytidine; D008464:Mecamylamine; D009538:Nicotine; D001285:Atropine